Project Summary Candidate My overarching goal is to bridge the gap between basic discoveries and the prevention and treatment of alcohol use disorders (AUD). Towards accomplishing that goal I have sought career and scientific opportunities that expose me to a variety of approaches to tackling AUD from molecular, behavioral and neural system perspectives. The major emphasis of my graduate training was developing sophisticated behavioral procedures that facilitate pharmacological manipulations and investigation of the molecular underpinnings of psychiatric and AUD. To unite this training with the deep biochemistry and molecular tools required to determine how epigenetic mechanisms contribute to AUD, I sought my post-doctoral training and research in the lab of Dr. Reinberg, who is a world-renowned leader in chromatin biology and transcription. My ultimate goal for the R00 phase is to become an independent investigator and tackle the root, epigenetic causes of AUD and make a large impact on their diagnosis, prevention and treatment. I plan to accomplish this by bridging disciplines so that I can approach AUD from molecular, behavioral and neural system perspectives. This K99/R00 application represents only the beginning of this work and I am most excited by its potential to discover novel molecular mechanisms in AUD through my genome-wide and biochemical approaches. Environment Dr. Reinberg's lab is a fantastic place to gain the experience I need to launch my future career as an independent investigator. Under his mentorship and through his dynamic lab, I will learn a host of sophisticated biochemistry and molecular biology techniques. Importantly, this lab is well established and has deep resources for probing challenging questions in chromatin biology. These well-established resources and expertise include all of the biochemistry and molecular biology techniques required for training in the studies I propose. One of the truly remarkable things about the Reinberg lab is the high caliber and deep expertise of its members working on a number of challenging questions requiring the development of innovative techniques and approaches. The environment in his lab dovetails nicely with the supportive environment at my host institution, my collaborators and the training that is sure to enrich my experience and propel my professional development Research Alcohol (ethanol, EtOH) use disorders (AUD) are characterized by heterogeneous genetic and behavioral underpinnings. Indeed, growing evidence suggests that disruptions in the underlying gene sequence can only partially account for the molecular profile of AUD. An emerging theme is that the expression profile of large gene networks is markedly altered in the alcoholic brain. Preliminary data and recent literature suggest that autism susceptibility candidate 2 (AUTS2) may represent one such key epigenetic regulator that drives aberrant transcriptional programs in AUD. This proposal examines how AUTS2 and associated chromatin dynamics drive transcriptional changes that may underlie specific AUD phenotypes. AIM1 will first identify the core components and chromatin dynamics of AUTS2-related complexes directly in C57Bl/6J (C57) neurons using a sophisticated biochemistry and molecular biology approach. Secondly, AIM1 will probe how these AUTS2-associated chromatin dynamics impact transcriptional regulation in the PFC of mice selectively bred for high and low EtOH preference (HAP and LAP mice, respectively) through ChIP-seq and RNA-seq. AIM 2 examines how the expression of AUTS2 itself is regulated in both mouse AUD models (i.e., HAP vs. LAP) and human neural culture that models an AUTS2 SNP associated with EtOH consumption and AUTS2 expression. AIM 3 identifies behavioral and molecular contributions of AUTS2 to AUD-associated behaviors in vivo through the generation of an inducible, Auts2-conditional knockout (CKO) mouse. Through this work, I hope to reveal how AUTS2 drives AUD transcriptional and behavioral phenotypes, providing guides for diagnostic and targeted interventions of AUD.